Abstract Depression is a highly prevalent in Parkinson's disease (PD) and is often said to contribute more to the lowered quality of life than the debilitating motor symptoms. Although the etiology of depression in PD is unknown, understanding the potential pathophysiological processes and deleterious consequences of these co-morbidities is of high importance, and may lead to the development of novel treatment therapies. Currently, models aimed at deciphering the complex neurobiological interactions of PD and depression are lacking. In the proposed studies, we will combine the unilateral 6-hydroxydopamine rat model of PD with a widely accepted rat model of stress-induced depression symptomology (chronic variable stress model), to test the hypothesis that experimental depression exacerbates the neurodegeneration and associated dysfunction of the injured mesostriatal dopaminergic system as evaluated by functional, morphological, neurochemical, and gene expression analyses. SPECIFIC AIM #1 will determine if stress-induced depression either following, preceding, or flanking neurotoxin lesioning exacerbates behavioral symptoms and dopaminergic neuronal degeneration and related behavioral and neurochemical sequelae in the injured mesostriatal system. SPECIFIC AIM #2 will assess whether antidepressant treatment improves or hinders midbrain dopaminergic neuron survival and associated parameters in the combined PD/chronic stress-induced depression model. SPECIFIC AIM #3 will determine if experimental induction of depression exacerbates behavioral and neurochemical dysfunction and dopaminergic neuronal degeneration to a greater extent in the injured mesostriatal system of old vs. young animals. To test a potential mechanism of action, SPECIFIC AIM #4 will use a glucocorticoid receptor antagonist currently in clinical trials for treatment of depression to determine if endogenous glucocorticoids released during stress mediate the deleterious effects of stress-induced depression in the injured mesostriatal system. In the context of the dopaminergic mesotelencephalic system, each of these aims will be addressed by using forelimb-use asymmetry behavioral tests, tyrosine hydroxylase immunohistochemistry, HPLC analysis of dopamine and its metabolites, and in situ hybridization for dopamine- associated neurotrophic factors. The overall goal of this project is to gain functional, morphological and mechanistic insight into the co-morbidity of PD, stress and depression. Moreover, this research may lead to future therapies that alleviate affective as well as motor symptoms of PD. Project Narrative Almost half of all patients with Parkinson's disease, the second-most common neurodegenerative disease in the US, experience coexisting major depression. The present research will investigate whether having depression worsens motor symptoms and hastens brain cell death in PD. This work will help us understand the underlying brain circuits, chemicals and mechanisms interacting in these two co-morbid disorders and may reveal novel therapeutic approaches to relieve both mood and motor symptoms of PD.